Asymmetric formal C–C bond insertion into aldehydes via copper-catalyzed diyne cyclization

The formal C–C bond insertion into aldehydes is an attractive methodology for the assembly of homologated carbonyl compounds. However, the homologation of aldehydes has been limited to diazo approach and the enantioselective reaction was rarely developed. Herein, we report an asymmetric formal C–C bond insertion into aldehydes through diyne cyclization strategy. In the presence of Cu(I)/SaBOX catalyst, this method leads to the efficient construction of versatile axially chiral naphthylpyrroles in moderate to excellent yields with good to excellent enantioselectivities. This protocol represents a rare example of asymmetric formal C–C bond insertion into aldehydes using non-diazo approach. The combined experimental and computational mechanistic studies reveal the reaction mechanism, origin of regioselectivity and stereoselectivity. Notably, the chiral phosphine ligand derived from synthesized axially chiral skeleton was proven to be applicable to asymmetric catalysis.

does not require the more hazardous diazo compounds.In this work, the authors proposed a pathway that goes through a reactive carbonyl ylide intermediate, which in turn allows rapid rearrangement to the desired formal insertion product.
While I have not spotted any serious flaw in the experimental procedure, claiming the current approach in the abstract and introduction as a homologation of aldehyde sounds like an overstatement to me.The current approach seems to heavily rely on diyne cyclization to generate a crucial reactive intermediate and I am not convinced about the generalizability of this method.In my point of view, the value of the current work lies mostly on the realization of highly enantioselective axial chirality control.

Major issues:
While I consider the experimental part to be generally acceptable, I have serious concerns on the computational effort.
-The major claim on the origin of enantioselectivity is based on the computed TS with SaBOX ligand (L4), namely TS_A-(R) and TS_A-(S) in Fig. 7.There are, however, serious inconsistencies in the chirality of ligands presented in the manuscript.While the chirality of ligand L4 in the Lewis structure on the bottom-right of Fig. 7 is consistent with the chirality of L4 in Table 2, the chirality of L4 in the ball-and-stick structure on the top-right of Fig. 7 is EXACTLY OPPOSITE.This means the presented computational result actually supports the enantioselectivity OPPOSITE to what the authors have claimed, if the computational results are taken as-is.
-A more concerning problem was revealed when I checked the optimized coordinates in the hope of confirming the chirality issue.Specifically, the bridgehead carbon next to each oxygen atom of L4 in the computational models (both TS_A-(R) and TS_A-(S)) had only THREE as opposed to usual four bonds (i.e. one proton was missing).While authors have not provided the total charge of the computed system nor the computed electronic energies for me re-validate and determine the actual influence to the computed geometry, this error is anyway unacceptable and should render the whole computational results on enantioselectivity untrustable.
-Even if we disregard the stated issues for now, the whole catalytic cycle is not in line with the SaBOX transition states used to explain the enantioselectivities.While I do understand the possible limitation in computing power that calls for a simplified model, the computational model used in the catalytic cycle uses a monodentate ligand (MeCN) while the SaBOX ligand of interest serves as a bidentate ligand.As coordination number and coordination geometry plays a very important role in organometallic reaction mechanisms, simply replacing the bidentate SaBOX with monodentate MeCN is unlikely to give comparable results.
Taking all these into account, I do believe that the current computational section is doing more harm than good, to the point that I would suggest a rejection of the current manuscript unless the authors remove the computational parts from the whole work.
While I do value the successful construction of axially chiral skeleton, I think more support for the carbonyl ylide intermediate should be provided in order to pose that as a generalizable strategy.The current approach is highly limited to the specific diyne substrate that I am strongly hesitant to simply classify it as "carbene equivalent" (e.g.quoted in bottom left corner of Fig. 1) and claim to be a "formal C-C bond insertion strategy".

Minor issues:
- -As both NMR and HPLC characterization are carried out on the mixture of isomers of 5u, which I assumed the authors have failed to separate the diastereomers, it is unclear to me how the correspondence of the 4 HPLC peaks are determined in order to calculate the presented dr and ee.

XIAMEN UNIVERSITY
Xiamen, Fujian, China This is a good suggestion.The statement mentioned has been corrected accordingly in the revised manuscript (Table 2).

(c) Original comments: Does Ms-protecting group not suitable in asymmetric version?
We thank reviewer 1's great suggestion!The suggested substrate with Ms-protecting group (4e) was synthesized and tested in the asymmetric transformation.It was found that substrate 4e demonstrated good reactivity under the standard reaction conditions, delivering axially chiral naphthylpyrrole 5e in 89% yield with 86% ee.This result has been added into the revised manuscript (Fig. 3).

(d) Original comments:
In reaction scope study (Fig 2), does this reaction works when R 1 and R 2 are alkyl groups or R 2 is alkyl group?
We appreciate this constructive suggestion!The suggested experiments have been carried out and their results were included in the revised supporting information (Supplementary Table 3).Consistent with our previous reports on diyne cyclization (J.Am.Chem.Soc.2019, 141, 16961; J. Am.Chem.Soc.2020, 142, 7618), alkyl substituted (R 2 = alkyl) diynes 1 were found to be not compatible in the transformation and most of them gave inseparable mixtures.It's clear that substrates bearing electron-rich aryl groups gave better results.The possible reason is that these aryl groups (R 2 = aryl) play a key role in stabilizing the vinyl cation intermediates for further trapping.
(e) Original comments: please cite the relevant reference (Angew. Chem. Int. Ed. 2023, 62, e202303670).This is a great suggestion!Actually, the mentioned reference has been cited in our original manuscript (ref 59).
We thank reviewer 1's great suggestions.The 1 H NMR spectra mentioned (3u, 3w) have been purified and their yields have also been adjusted.The corresponding spectra and yields were updated in the revised manuscript and supporting information.

II. Response to reviewer 2: (a) Original comments: This manuscript describes an asymmetric formal C-C bond insertion into aldehydes through diyne cyclization strategy with Cu(I)/SaBOX as the catalyst, providing a series of homologated pyrrylaldehydes and axially chiral naphthylpyrroles in moderate to good yields with good to high enantioselectivities. The key of the ingenious design is the vinyl cation intermediate generated from diyne cyclization which is used as the precursor of reactive carbonyl ylide with electron-rich substituents in replacement of diazo compounds.
Moreover, the experimental and computational mechanistic studies were also conducted to reveal the reaction mechanism.This work offers an alternative protocol to achieve asymmetric formal C-C bond insertion into aldehydes utilizing non-diazo approach.The manuscript is well written and the experiments are carefully performed.Thus, I am convinced that this manuscript is of interest for the broad readership of Nat.Commun.The publication of this work in Nat.Commun. is recommended after authors addressing the following concerns and questions.
We appreciate reviewer 2's generous support!(b) Original comments: The diastereoselectivities of 5s-5u are still unsatisfied due to the challenge of construction of quaternary carbon stereocenter.Did the authors ever try to examine the formaldehyde to avoid the issue?
We appreciate this suggestion!The suggested reaction using formaldehyde has been carried out, however no product was observed.The low nucleophilicity of formaldehyde could be the reason for the poor result.Moreover, systematic evaluation of more aryl aldehydes were conducted and most of these aryl aldehydes gave relatively low yields with 1:1-2:1 dr, which might due to the direct intermolecular attack of these nucleophiles onto ynamides.The suitable nucleophilicity of aldehyde is necessary for the atroposelective transformation.Thus, the diastereocontrol involving the quaternary carbon stereocenter is still challenging at this stage.These results have been included in the revised supporting information (Supplementary Table 4).
(c) Original comments: The naphthylpyrrole product 12 was transformed to an axially chiral phosphine ligand 14, which was used in [3+2]  As suggested, classic phosphine ligands were selected based on above references, and the target reactions have been conducted for comparison.As for [3+2] cycloaddition, our axially chiral monophosphine ligand 14 demonstrated better reactivity and higher enantioselectivity than bisphosphine ligand (S,S)-Ph-BPE and monophosphine ligand (S)-N-i Pr2-MonoPhos.As for allylic alkylation, our axially chiral monophosphine ligand 14 showed higher reactivity and lower enantioselectivity than bisphosphine ligand (S,S)-Ph-BPE and monophosphine ligand (S)-N-i Pr2-MonoPhos.Therefore, our axially chiral monophosphine ligand 14 or its skeleton is potentially useful in asymmetric catalysis.These results have been included into the revised manuscript (Fig. 5).

(d) Original comments:
The NMR spectra of 3s, 3u, 3w, 9 and 11 show signals that hint to some impurities.These compounds should be re-purified and the yields adjusted.
We thank reviewer 2's suggestion.Compounds 3s, 3u, 3w, 9 and 11 have been purified accordingly.Their updated NMR spectra and yields were included into the revised manuscript and supporting information.

III. Response to reviewer 3:
(a) Original comments: The manuscript "Asymmetric formal C -C bond insertion into aldehydes via copper-catalyzed diyne cyclization" by Zhou and coworkers reports an alternative method for homologation of aldehyde that does not require the more hazardous diazo compounds.In this work, the authors proposed a pathway that goes through a reactive carbonyl ylide intermediate, which in turn allows rapid rearrangement to the desired formal insertion product.While I have not spotted any serious flaw in the experimental procedure, claiming the current approach in the abstract and introduction as a homologation of aldehyde sounds like an overstatement to me.The current approach seems to heavily rely on diyne cyclization to generate a crucial reactive intermediate and I am not convinced about the generalizability of this method.In my point of view, the value of the current work lies mostly on the realization of highly enantioselective axial chirality control.
We appreciate reviewer 3's kind comments and generous support on our work!Indeed, this atroposelective transformation relies on the unique vinyl cation intermediate generated from diyne cyclization, enabling the preparation of axially chiral naphthylpyrroles.Further investigation into simpler starting materials and intermolecular reactions are ongoing in our laboratory.
(b) Original comments: While I consider the experimental part to be generally acceptable, I have serious concerns on the computational effort.
-The major claim on the origin of enantioselectivity is based on the computed TS with SaBOX ligand (L4), namely TS_A-(R) and TS_A-(S) in Fig. 7.There are, however, serious Xiamen, Fujian, China inconsistencies in the chirality of ligands presented in the manuscript.While the chirality of ligand L4 in the Lewis structure on the bottom-right of Fig. 7 is consistent with the chirality of L4 in Table 2, the chirality of L4 in the ball-and-stick structure on the top-right of Fig. 7 is EXACTLY OPPOSITE.This means the presented computational result actually supports the enantioselectivity OPPOSITE to what the authors have claimed, if the computational results are taken as-is.
We strongly appreciate reviewer 3's careful and thorough inspections, which helped us a lot to improve the computational studies.We apologize for the serious mistakes on chiral ligand L4 and the attached XYZ coordinates in our computational results during editing.To correct these errors, we recalculated the whole reaction and double-checked the chirality of ligand and the enantioselectivity of reaction (the calculations supported our observed enantioselectivity well).These results have been included into the revised manuscript (Fig. 7) and supporting information (Supplementary Figure 1-2).

(c) Original comments:
-A more concerning problem was revealed when I checked the optimized coordinates in the hope of confirming the chirality issue.Specifically, the bridgehead carbon next to each oxygen atom of L4 in the computational models (both TS_A-(R) and TS_A-(S)) had only THREE as opposed to usual four bonds (i.e. one proton was missing).While authors have not provided the total charge of the computed system nor the computed electronic energies for me re-validate and determine the actual influence to the computed geometry, this error is anyway unacceptable and should render the whole computational results on enantioselectivity untrustable.
We apologize for the serious mistakes for chiral ligand L4 and the attached XYZ coordinates in our computational studies during editing.To correct these mistakes, we recalculated the whole reaction and double-checked the structure of ligand and the enantioselectivity of reaction.
Additionally, the total charge of the computed system and computed electronic energies have all been added in the updated computational results.These results have been included into the revised manuscript (Fig. 7) and supporting information (Supplementary Figure 1-2).

(d) Original comments: -Even if we disregard the stated issues for now, the whole catalytic cycle is not in line with the SaBOX transition states used to explain the enantioselectivities. While I do understand the possible limitation in computing power that calls for a simplified model, the computational model used in the catalytic cycle uses a monodentate ligand (MeCN) while the SaBOX ligand of interest serves as a bidentate ligand. As coordination number and coordination geometry plays a very important role in organometallic reaction mechanisms, simply replacing the bidentate SaBOX with monodentate MeCN is unlikely to give comparable results.
Taking all these into account, I do believe that the current computational section is doing more harm than good, to the point that I would suggest a rejection of the current manuscript unless the authors remove the computational parts from the whole work.Xiamen, Fujian, China We thank this excellent question!We agree that the simplified model using MeCN as ligand could give different results compared with the bidentate SaBOX.To be responsible for our study, we recalculated the whole system using SaBOX as ligand and double-checked all the results (the calculations supported our enantioselective reaction well, Fig. 7).
To be consistent with the whole work, we wish to include the new computational studies in the revised manuscript and supporting information (as highlighted in the revised manuscript and SI), if the reviewer agrees.Otherwise, we can put them only into supporting information.
(e) Original comments: While I do value the successful construction of axially chiral skeleton, I think more support for the carbonyl ylide intermediate should be provided in order to pose that as a generalizable strategy.The current approach is highly limited to the specific diyne substrate that I am strongly hesitant to simply classify it as "carbene equivalent" (e.g.quoted in bottom left corner of Fig. 1) and claim to be a "formal C-C bond insertion strategy".
We thank reviewer 3's intriguing suggestions!We agree with reviewer 3 for the carbonyl ylide intermediate and believe it's the key for the transformation.While carbonyl ylide intermediate is hard to be directly obtained through experimental approaches, our updated computational studies have been conducted, which supported the formation of carbonyl ylide intermediate (or its resonance form) with low energy barrier.
To avoid misunderstanding, we changed the statement of vinyl cation from "carbene equivalent" to "carbene-like intermediate" in Fig. 1 (For related statement of "carbene-like" on vinyl cations, see: Angew.Chem.Int. Ed. 2018, 57, 16942;Sci. China Chem. 2022, 65, 20).Indeed, the current approach is still limited to diyne substrates and further investigations into simpler precursors and intermolecular reactions are ongoing.From the view of aldehydes (both substrates and products), this reaction could be considered as the formal C-C bond insertion into aldehydes based on carbene-like intermediate (vinyl cation), although with limitations.The statement mentioned has been changed accordingly in the revised manuscript (Fig. 1 and related text).We apologize for the misunderstanding caused by our statement.In our original manuscript, [Cu] represents a ligated cooper species with a positive charge.To avoid confusions, we have corrected [Cu] to Cu + L4 and [Cu] -to CuL4 in the revised manuscript (Fig. 7) and supporting information (Supplementary Figure 1).
(g) Original comments: As both NMR and HPLC characterization are carried out on the mixture of isomers of 5u, which I assumed the authors have failed to separate the Xiamen, Fujian, China diastereomers, it is unclear to me how the correspondence of the 4 HPLC peaks are determined in order to calculate the presented dr and ee.
We thank reviewer 3's great comments.Extensive efforts have been made to separate the diastereomers of compound 5v, but they cannot be isolated well (the number of 5u was changed to 5v in the revised manuscript, because of the incorporation of a new Ms-protected example 5e according to another reviewer's comments).After multiple attempts, we got the diastereomers of 5v with higher dr (2.5:1), which gave clearer NMR and HPLC spectra.These NMR and HPLC spectra have been included into the revised supporting information.
Here are the details for the calculation of dr and ee: (1) The dr of 5v was calculated from the analysis into crude 1 H NMR of reaction mixture before purification.As shown below, the integration in crude 1 H NMR of reaction mixture shows a ratio of 1.4:1 for diastereomers, and this dr ratio is consistent with the 1 H NMR for the mixture of diastereomers after quick column chromatography.
results have been included into the revised manuscript (Fig. 7) and SI (Supplementary Figure 1-2).
(c) Original comments: (2) Again for the process between F and A, stating the energies on the state would lead to the illusion that F->A is energetically unfavourable (because the relative Gibbs free energy goes from -56.4 to -35.1), but I supposed it is not the case (otherwise the whole catalytic reaction would not occur spontaneously).It would be more appropriate to draw the free energy landscape of one catalytic cycle (from A to A), following the standard practice in the field, so that readers can appreciate not just the free energy change in individual steps, but also the free energy gain over one cycle (which is not shown in the current presentation).
We thank reviewer 3's helpful suggestion.The mentioned catalytic cycle has been changed and included into the revised manuscript (Fig. 7) and SI (Supplementary Figure 1-2).

(d) Original comments:
(3) The process 1,4-H migration and demetallation is simply not shown in the calculation and is only briefly stated in the catalytic cycle.However, considering the great change in the Cu position, it is hard to believe the process is trivial enough to be safely omitted.This is a good question!As suggested, we recalculated 1,4-H migration and demetallation process.During the calculation, we found the direct 1,4-H migration without any mediator has a very high energy barrier.Inspired by our previous work involving Lewis base-assisted 1,4-H migration (Angew.Chem.Int. Ed. 2023, 62, e202303670;Chem. Sci. 2021, 12, 9466), we finally found aldehyde could act as Lewis base to promote the 1,4-proton transfer step (energy barrier 18.7 kcal/mol) and following demetallation step has a very low energy barrier according to our previous study.
To be more accurate, we independently calculated the catalytic cycle of desired product with two opposite configurations ((R)-5f, major and (S)-5f, minor).Consistent with previous results, the diyne cyclization is the enantio-determining step (from intermediate A to B), and ring-opening of 1,3-dioxolane is the rate-determining step (from intermediate F to G).These results have been included into the revised manuscript (Fig. 7) and SI (Supplementary Figure 1-2).
(e) Original comments: (4) Authors should double check the accuracy of presentation of the mechanistic cycle.There are still inconsistencies between the presented state and the computational results.For example, it is shown in the catalytic cycle that B + 2h -> C, but B and C actually contains the same number of atoms in the computational results (because state "B" already contains 2h).
We thank reviewer 3's thorough inspections!We've recalculated the intermediate B according to the suggestions, and double-checked our updated mechanistic cycle.These results have been included into the revised manuscript (Fig. 7) and SI (Supplementary Figure 1-2).
(f) Original comments: (5) I personally still have doubts on the state F and TS_F, considering the atypical bond transformations.Though I currently do not have alternative suggestions, and would reconsider the situation after the authors have addressed the issue in (2).We thank reviewer 3's suggestion.Further DFT calculations have been carried out to figure out other possible cationic intermediates and transition states (such as the related oxonium intermediate shown below), however we cannot locate those intermediates and transition states.The pathway through transition state F (the number changed to G in updated manuscript) shows the best result currently.
The authors should clearly indicate what [Cu] means in the manuscript, especially the charge it implies.If [Cu] is not a neutral species (which I supposed it is not), the [Cu]-notation in places like the intermediate C in Fig 7 would be confusing.

( f )
Original comments: -The authors should clearly indicate what [Cu] means in the manuscript, especially the charge it implies.If [Cu] is not a neutral species (which I supposed it is not), the [Cu]-notation in places like the intermediate C in Fig 7 would be confusing.

I. Response to reviewer 1: (a) Original comments: In this
however, the present reaction is conceptually different from the previous one and the final product is more complex aldehyde.Overall, the manuscript is well presented and has merit for publication in Nature Communication after minor revision.We appreciate reviewer 1's kind support and excellent comments!

(b) Original comments: Table
-2, E.e correct should be corrected to ee.